The present invention relates to a process for the preparation of symmetrical diacylhydrazines.
More specifically, the present invention relates to a process for the preparation of symmetrical diacylhydrazines comprising the reaction of an ester with hydrazine, in its pure or hydrated state, to give a monoacylhydrazine which is subsequently reacted with a xcex2-ketoester obtaining the desired symmetrical diacylhydrazine.
A further object of the present invention relates to the symmetrical diacylhydrazines obtained with the above process.
Various processes for the preparation of symmetrical diacylhydrazines are known in the art.
For example, the preparation of symmetrical diacylhydrazines can be easily effected by the reaction of hydrazine with acyl chlorides having general formula (Ia):
Rxe2x80x94COxe2x80x94Clxe2x80x83xe2x80x83(Ia)
wherein R represents a linear or branched C1-C18 alkyl group, or an aryl group, operating according to the following reaction scheme (Scheme 1):
2Rxe2x80x94COxe2x80x94Cl+1NH2NH2xe2x86x921Rxe2x80x94COxe2x80x94NHxe2x80x94NHxe2x80x94COxe2x80x94R+2Hxe2x80x94Cl;
or by the reaction of the above hydrazine with anhydrides of carboxylic acids having general formula (Ib):
Rxe2x80x94COxe2x80x94Oxe2x80x94COxe2x80x94Rxe2x80x83xe2x80x83(Ib)
wherein R has the same meanings described above, according to the following reaction scheme (Scheme 2):
2Rxe2x80x94COxe2x80x94Oxe2x80x94COxe2x80x94R+1NH2NH2xe2x86x921Rxe2x80x94COxe2x80x94NHxe2x80x94NHxe2x80x94COxe2x80x94R+2Rxe2x80x94COOH;
as described, for example, in Houben Weyl (1967) Band 10/2, pages 127-135; and in Patai (1970): xe2x80x9cThe Chemistry of Amidesxe2x80x9d, Chapter 10, pages 533-535.
It is also known that, from the reaction of the acyl chlorides having general formula (Ia) described above, or anhydrides of carboxylic acids having general formula (Ib) described above, with hydrazine, operating with a molar ratio acyl chloride having general formula (Ia):hydrazine or anhydride of a carboxylic acid having general formula (Ib):hydrazine 1:1, according to the following reaction schemes (Scheme 3 and Scheme 4):
1Rxe2x80x94COxe2x80x94Cl+1NH2NH2xe2x86x921Rxe2x80x94COxe2x80x94NHxe2x80x94NH2+1Hxe2x80x94Cl; 
1Rxe2x80x94COxe2x80x94Oxe2x80x94COxe2x80x94R+1NH2NH2xe2x86x921Rxe2x80x94COxe2x80x94NHxe2x80x94NH2+1Rxe2x80x94COOH;
monoacylhydrazines having general formula (IC) are obtained:
Rxe2x80x94COxe2x80x94NHxe2x80x94NH2xe2x80x83xe2x80x83(Ic)
wherein R has the same meanings described above.
It is also possible to prepare mixed diacylhydrazines by reacting the monoacylhydrazines having general formula (Ic) described above, with an acyl chloride having general formula (Id):
Rxe2x80x2xe2x80x94COxe2x80x94Clxe2x80x83xe2x80x83(Id)
wherein Rxe2x80x2 has the same meanings as R described above, on the condition that R and Rxe2x80x2 are different from each other, according to the following reaction scheme (Scheme 5):
1Rxe2x80x94COxe2x80x94NHxe2x80x94NH2+1Rxe2x80x2xe2x80x94COxe2x80x94Clxe2x86x921Rxe2x80x94COxe2x80x94NHxe2x80x94NHxe2x80x94COxe2x80x94Rxe2x80x2+1Hxe2x80x94Cl.
It is also known that the reaction of the hydrazine with esters of carboxylic acids having general formula (Ie):
Rxe2x80x94COxe2x80x94ORxe2x80x3xe2x80x83xe2x80x83(Ie)
wherein R has the same meanings described above and Rxe2x80x3 represents a linear or branched C1-C18 alkyl group, generally leads to the formation of monoacylhydrazines having general formula (Ic) described above, according to the following reaction scheme (Scheme 6)
1Rxe2x80x94COxe2x80x94ORxe2x80x3+1NH2NH2xe2x86x921Rxe2x80x94COxe2x80x94NHxe2x80x94NH2+1Rxe2x80x3xe2x80x94OH;
as described, for example, in Houben Weyl (1952) Band 8, page 676-679; and in Patai (1970): xe2x80x9cThe Chemistry of Amidesxe2x80x9d, Chapter 10, pages 527-532. This reaction generally takes place using hydrated hydrazine (64% hydrazine; 36% water), in the presence of a polar solvent such as, for example, methanol, ethanol, dimethylformamide, water, etc. This hydrated hydrazine is a commonly used commercial product.
When the operation is carried out according to Scheme 6, the subsequent insertion of a second acyl group is generally very difficult and, when this insertion is possible, it is necessary to operate at high temperatures, for long reaction times and with the addition of acid catalysts.
In addition, in most cases, operating according to Scheme 6, the monoacylhydrazine which is formed by filtration or distillation of the reaction solvent and alcohol produced during the reaction, must be isolated. The formation of the symmetrical diacylhydrazine subsequently takes place by the elimination of a hydrazine mole from two moles of monoacylhydrazine having general formula (Ic) operating according to the following reaction scheme (Scheme 7):
2Rxe2x80x94COxe2x80x94NHxe2x80x94NH2xe2x86x92Rxe2x80x94COxe2x80x94NHxe2x80x94NHxe2x80x94COxe2x80x94R+NH2xe2x80x94NH2
as described, for example, in Houben Weyl (1967) Band 10/2, pages 127-128.
Operating according to Scheme 7 above, in order to favour the progression of the reaction, the anhydrous hydrazine which is released, must be removed by distillation. As the distillation temperature of the anhydrous hydrazine is 113.5xc2x0 C., it is necessary to use reaction temperatures of at least 150xc2x0 C. and a high-boiling reaction solvent in order to be able to remove all the hydrazine released by the reaction, by means of distillation.
The elimination of the last percentages of hydrazine is very slow and consequently, owing to the high operating temperatures and long reaction times, numerous secondary products are formed which cause low yields and purities of the crystallized product obtained which rarely exceed 98%.
The undesired secondary products formed when operating according to Scheme 7 are tetrazine derivatives having the following general formulae (If) and (Ig) 
wherein R has the same meanings defined above.
Or, in order to obtain diacylhydrazines, the monoacyl-hydrazine having general formula (Ic) can be reacted with a mole of acyl chloride having general formula (Ia), or with a mole of an anhydride of a carboxylic acid having general formula (Ib), operating according to the following reaction schemes (Scheme 8 and Scheme 9):
1Rxe2x80x94COxe2x80x94NHxe2x80x94NH2+1Rxe2x80x94COxe2x80x94Clxe2x86x921Rxe2x80x94COxe2x80x94NHxe2x80x94NHxe2x80x94COxe2x80x94R+1Hxe2x80x94Cl;
1Rxe2x80x94COxe2x80x94NHxe2x80x94NH2+1Rxe2x80x94COxe2x80x94Oxe2x80x94COxe2x80x94Rxe2x86x921Rxe2x80x94COxe2x80x94NHxe2x80x94NHxe2x80x94COxe2x80x94R+1Rxe2x80x94COOH.
The Applicant has now found a process for the preparation of symmetrical diacylhydrazines comprising the reaction of an ester with hydrazine, in its pure or hydrated state, to give a monoacylhydrazine which is subsequently reacted with a xcex2-ketoester obtaining the desired symmetrical diacylhydrazine, capable of overcoming the disadvantages of the known art.
The present invention therefore relates to a process for the preparation of symmetrical diacylhydrazines having general formula (I):
R1xe2x80x94COxe2x80x94NHxe2x80x94NHxe2x80x94COxe2x80x94R1xe2x80x83xe2x80x83(I)
wherein:
R1 represents a linear or branched C1-C18 alkyl group; a linear or branched C2-C8 alkoxyalkyl group; a C2-C8 cyanoalkyl group; a C5-C8 cycloalkyl group, said cycloalkyl group optionally containing a heteroatom selected from oxygen, nitrogen and sulfur; a C6-C18 aryl group; a C7-C20 arylalkyl or alkylaryl group, said arylalkyl or alkylaryl groups optionally substituted with one or more hydroxyl groups, or with one or more linear or branched C1-C8 alkoxyl groups; comprising:
(A) reacting an ester of a carboxylic acid having general formula (II):
R1xe2x80x94COxe2x80x94OR2xe2x80x83xe2x80x83(II)
wherein R1 has the same meanings defined above and R2 represents a linear or branched C1-C18 alkyl group, with hydrazine, in its pure or hydrated state, obtaining a monoacylhydrazine having general formula (III):
R1xe2x80x94COxe2x80x94NHxe2x80x94NH2xe2x80x83xe2x80x83(III);
(B) reacting the monoacylhydrazine having general formula (III) obtained in step (A), with a xcex2-ketoester having general formula (IV):
R3xe2x80x94COxe2x80x94CH2xe2x80x94COOR4xe2x80x83xe2x80x83(IV)
wherein R3 represents a linear or branched C1-C18 alkyl group, or a C6-C18 aryl group and R4 represents a linear or branched C1-C18 alkyl group, obtaining the desired symmetrical diacylhydrazine having general formula (I).
Examples of C1-C18 alkyl groups are: methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, t-butyl, isobutyl, t-amyl, isoamyl, 2-ethylhexyl, n-octyl, 1,1,3,3-tetramethylbutyl, n-dodecyl, 1,1,7,7-tetramethyloctyl, n-octadecyl, etc.
Examples of C2-C8 alkoxyalkyl groups are: methoxyethyl, ethoxylethyl, ethoxypropyl, etc.
Examples of C2-C8 cyanoalkyl groups are: cyanomethyl, cyanoethyl, cyanopropyl, etc.
Examples of C5-C8 cycloalkyl groups, optionally containing a heteroatom, are: cyclopentyl, cyclohexyl, morpholinyl, piperidyl, etc.
Examples of C6-C18 aryl groups are: phenyl, naphthyl, anthracenyl, 2-hydroxyphenyl, etc.
Examples of C7-C20 arylalkyl or alkylaryl groups are: benzyl, 2-phenylethyl, 4-t-butylbenzyl, etc.
Examples of C1-C8 alkoxyl groups are: methoxyl, ethoxyl, propoxyl, n-butoxyl, etc.
In step (A) of the process object of the present invention the ester of carboxylic acid having general formula (II) and the hydrazine, in its pure or hydrated state, are used in molar ratios ranging from 1:1 to 1:6, preferably ranging from 1:1.1 to 1:4.
Step (A) is carried out in the presence of a polar organic solvent such as, for example, methanol, ethanol, n-butanol, dimethylformamide, water, or in the presence of a mixture of these polar organic solvents, at a temperature ranging from 10xc2x0 C. to 150xc2x0 C., preferably at a temperature ranging from 10xc2x0 C. to 65xc2x0 C. in the case of methanol, at a temperature ranging from 10xc2x0 C. to 78xc2x0 C. in the case of ethanol, at a temperature ranging from 10xc2x0 C. to 100xc2x0 C. in the case of water, butanol and dimethylformamide, for a time ranging from 0.5 hours to 15 hours, preferably from 1 hour to 10 hours.
Step (A) of the process object of the present invention can also be carried out in the presence of a mixture of the above polar organic solvents with hydrocarbon solvents such as, for example, toluene, xylene, etc., using a weight ratio polar organic solvent:hydrocarbon solvent ranging from 85:15 to 15:85, at a temperature ranging from 10xc2x0 C. to 150xc2x0 C., preferably from 50xc2x0 C. to 100xc2x0 C.
The monoacylhydrazine having general formula (III) obtained in step (A) is isolated, in its raw state, by means of two processes:
by filtration of said monoacylhydrazine previously precipitated by cooling to a temperature ranging from 0xc2x0 C. to 20xc2x0 C.; or,
by distillation of the hydrazine in excess and of the polar organic solvent which is partly or completely substituted with a higher-boiling hydrocarbon solvent, preferably toluene or xylene, without the need for crystallization.
When the isolation is carried out by distillation, the procedure is as follows:
distillation of the reaction solvent (polar organic solvent) and contemporaneous addition, by means of a drip funnel, of a hydrocarbon solvent in a quantity sufficient to allow the reaction mass to be stirred;
increase in the distillation temperature owing to the removal of the polar organic solvent, until the boiling point of the pure hydrocarbon solvent is reached and subsequent passage to step (B) described above, directly using the solution or suspension of the monoacylhydrazine having general formula (III) in the hydrocarbon solvent obtained at the end of the above distillation.
Alternatively, as already mentioned above, the monoacylhydrazine having general formula (III) obtained in step (A), can be isolated, in its raw state, by filtration of the precipitate obtained in step (A) by cooling to room temperature and subsequent washing with water to remove the excess hydrazine.
In step (B) of the process object of the present invention, the monoacylhydrazine having general formula (III) and the xcex2-ketoester having general formula (IV) are used in molar ratios ranging from 1:0.2 to 1:1.1, preferably from 1:0.5 to 1:0.8.
Said step (B) is carried out in the presence of an organic solvent of the hydrocarbon type such as, for example, toluene, xylene, iso-octane, cyclohexane, methylcyclohexane, nonane, decane, undecane, decaline, etc., at the reflux temperature of the solvent ranging from 60xc2x0 C. to 180xc2x0 C., for a time ranging from 20 minutes to 15 hours, preferably from 20 minutes to 12 hours, obtaining the desired symmetrical diacylhydrazine having general formula (I), an alkyl-pyrazolone or an aryl-pyrazolone having general formula (V), an alcohol having general formula (VI) and water as indicated in the following reaction scheme: 
wherein R1, R3 and R4 have the same meanings described above.
The reaction water which is formed in step (B) is separated by azeotropic distillation.
The above organic solvent of the hydrocarbon type is added operating as follows:
when the monoacyihydrazine having general formula (III) is isolated by filtration, it is added directly to the raw monoacylhydrazine obtained;
when the monoacylhydrazine having general formula (III) is isolated by distillation, it is added during the distillation of the polar organic solvent (as already described above).
A precipitate is formed in the reaction mass, during step (B) above, which consists of:
about 10%-40% of alkyl-pyrazolone or aryl-pyrazolone having general formula (V); and
about 60%-90% of symmetrical diacylhydrazine having general formula (I).
The reaction yield is usually very high and there is no formation of undesired secondary products such as, for example, the tetrazine compounds having general formula (If) and (Ig) described above.
The above reaction mass can be directly subjected to the treatment described hereunder to separate the symmetrical diacylhydrazine having general formula (I) from the alkyl-pyrazolone or aryl-pyrazolone having general formula (V).
Or, the above precipitate can be isolated from the reaction mass, after this is cooled to 0xc2x0 C.-50xc2x0 C., by means of filtration and drying in an oven at 50xc2x0 C.-100xc2x0 C., preferably 70xc2x0 C.-90xc2x0 C., under vacuum. In this case, a hydrocarbon solvent immiscible in water such as, for example, toluene, xylene, etc. is added to the precipitate thus isolated, which is then subjected to the treatment described hereunder to separate the symmetrical diacylhydrazine having general formula (I) from the alkyl-pyrazolone or aryl-pyrazolone having general formula (V).
The separation of the symmetrical diacylhydrazine having general formula (I) from the alkyl-pyrazolone or aryl-pyrazolone having general formula (V), can be effected by means of one or more hot aqueous washings, at a temperature ranging from 85xc2x0 C. to 125xc2x0 C., at a pressure ranging from 1 kg/cm2 to 4 kg/cm2: the alkyl-pyrazolone or aryl-pyrazolone passes into the aqueous phase in which it is soluble under heat. If the passage of the alkyl-pyrazolone or aryl-pyrazolone into the hot aqueous phase is insufficient, it is possible to carry out an additional washing with a diluted acid solution, at a concentration ranging from 2% to 10%, preferably from 4% to 8%, of a strong inorganic acid such as, for example, hydrochloric acid or sulfuric acid, operating at the same temperature and pressure at which the above hot aqueous washing is effected.
Alternatively, the separation of the symmetrical diacylhydrazine having general formula (I) from the alkyl-pyrazolone or aryl-pyrazolone having general formula (V) can be effected by means of a washing with a diluted acid solution, at a concentration ranging from 2% to 10%, preferably from 4% to 8%, of a strong inorganic acid such as, for example, hydrochloric acid or sulfuric acid, at a temperature ranging from 80xc2x0 C. to 90xc2x0 C., preferably from 84xc2x0 C. to 86xc2x0 C., at atmospheric pressure. To favour this washing, a C4-C5 alcohol can be optionally added to improve the solubility of the symmetrical diacylhydrazine in the organic phase. A hot aqueous washing is then effected at the same temperature as the above acid washing, at atmospheric pressure.
At the end of the above washings, during which the alkyl-pyrazolone or aryl-pyrazolone having general formula (V) is extracted from the organic phase, this phase, containing only the symmetrical diacylhydrazine having general formula (I), is anhydrified by distillation, heating to 100xc2x0 C.-110xc2x0 C., preferably 100xc2x0 C.-105xc2x0 C. The symmetrical diacylhydrazine having general formula (I) is subsequently crystallized by cooling to 50xc2x0 C.-10xc2x0 C., preferably 20xc2x0 C.-0xc2x0 C., and is then filtered, washed with the same reaction solvent and dried in an oven at 50xc2x0 C.-100xc2x0 C., preferably 70xc2x0 C.-90xc2x0 C., under vacuum.
Step (B) above, when the monoacylhydrazine having general formula (III) is isolated in its raw state by filtration, can also be carried out in the presence of a polar organic solvent such as, for example, butanol, propanol, amyl alcohol, dimethylformamide, etc. In this case, during the reaction which is carried out at reflux temperature, there is no separation of the reaction water and the reaction mass proves to consist of a solution without a precipitate. Upon subsequent cooling to 0xc2x0 C., the symmetrical diacylhydrazine having general formula (I) and the alkyl-pyrazolone or aryl-pyrazolone having general formula (V) precipitate: the precipitate is filtered and dried in an oven at 50xc2x0 C.-100xc2x0 C., preferably 70xc2x0 C.-90xc2x0 C., under vacuum. A hydrocarbon solvent immiscible with water such as, for example toluene, xylene, etc. is added to the precipitate thus isolated, which is then subjected to the treatment described above to separate the symmetrical diacylhydrazine having general formula (I) from the alkyl-pyrazolone or aryl-pyrazolone having general formula (V).
The symmetrical diacylhydrazine having general formula (I) obtained with the process object of the present invention, has a purity of over 98.0%. The reaction yield is over 85% when it refers to the quantity of monoacylhydrazine having general formula (III) used in step (B) of the above process and over 70% when it refers to the quantity of ester having general formula (II) used in step (A) of the above process.
The hydrazine, in its pure or hydrated state, used in step (A) of the process object of the present invention, is a product which is commercially available.
Examples of esters having general formula (II) which can be used in step (A) of the process object of the present invention are: methyl or ethyl acetate, methyl or ethyl butyrate, methyl or ethyl cyanoacetate, methyl or ethyl propionate, methyl or ethyl octanoate, methyl or ethyl benzoate, methyl or ethyl dodecanoate, methyl or ethyl salicylate, methyl 4-methyl-benzoate, ethyl isoamylacetate, ethyl phenylacetate, methyl 3-(3,5-di-t-butyl-4-hydroxyphenyl)-propionate, etc.
The above esters having general formula (II) are commercially available, or they can be prepared according to processes known in the art.
Examples of monoacylhydrazines having general formula (III), obtained in step (A) of the process object of the present invention, are: acetylhydrazine, cyanoacetylhydrazine, butyrylhydrazine, propionylhydrazine, n-octanoylhydrazine, isoamylacetylhydrazine, glycolylhydrazine, benzoylhydrazine, 4-methylbenzoylhydrazine, salicyloylhydrazine, dodecanoylhydrazine, phenylacetylhydrazine, 3-(3,5-di-t-butyl-4-hydroxyphenyl)propionylhydrazine, etc.
The above monoacylhydrazines having general formula (III) can also be commercially available: in this case, step (A) of the process object of the present invention is not effected.
A further object of the present invention therefore relates to a process for the preparation of symmetrical diacylhydrazines having general formula (I) described above, comprising the reaction of a monoacylhydrazine having general formula (III) described above, with a xcex2-ketoester having general formula (IV) described above, operating according to what is described for step (B).
Examples of xcex2-ketoesters having general formula (IV) which can be used in step (B) of the process object of the present invention, are: methyl acetoacetate, ethyl acetoacetate, t-butyl acetoacetate, ethyl benzoyl acetate, etc.
The above xcex2-ketoesters having general formula (IV) are commercially available.
Specific examples of symmetrical diacylhydrazines having general formula (I) which can be obtained with the process object of the present invention, but which in no way limit its scope, are: 1,2-di-propionylhydrazine, 1,2-di-butyrylhydrazine, 1,2-di-isoamylacetylhydrazine, 1,2-di-glycolylhydrazine, 1,2-di-acetylhydrazine, 1,2-di-n-octanoylhydrazine, 1,2-di-benzoylhydrazine, 1,2-di-salicyloylhydrazine, 1,2-di-dodecanoylhydrazine, 1,2-diphenylacetylhydrazine, 1,2-di-p-toluoylhydrazine, N,Nxe2x80x2-bis-[3-(3,5-di-t-butyl-4-hydroxyphenyl)propionyl]hydrazine, etc.
Some illustrative examples are provided for a better understanding of the present invention and for its embodiment but in no way limit the scope of the invention itself.